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A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci.

ABSTRACT: Body mass index (BMI), a proxy measure for obesity, is determined by both environmental (including ethnicity, age, and sex) and genetic factors, with > 400 BMI-associated loci identified to date. However, the impact, interplay, and underlying biological mechanisms among BMI, environment, genetics, and ancestry are not completely understood. To further examine these relationships, we utilized 427,509 calendar year-averaged BMI measurements from 100,418 adults from the single large multiethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We observed substantial independent ancestry and nationality differences, including ancestry principal component interactions and nonlinear effects. To increase the list of BMI-associated variants before assessing other differences, we conducted a genome-wide association study (GWAS) in GERA, with replication in the Genetic Investigation of Anthropomorphic Traits (GIANT) consortium combined with the UK Biobank (UKB), followed by GWAS in GERA combined with GIANT, with replication in the UKB. We discovered 30 novel independent BMI loci (P < 5.0 × 10-8) that replicated. We then assessed the proportion of BMI variance explained by sex in the UKB using previously identified loci compared to previously and newly identified loci and found slight increases: from 3.0 to 3.3% for males and from 2.7 to 3.0% for females. Further, the variance explained by previously and newly identified variants decreased with increasing age in the GERA and UKB cohorts, echoed in the variance explained by the entire genome, which also showed gene-age interaction effects. Finally, we conducted a tissue expression QTL enrichment analysis, which revealed that GWAS BMI-associated variants were enriched in the cerebellum, consistent with prior work in humans and mice.

SUBMITTER: Hoffmann TJ

PROVIDER: S-EPMC6216593 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci.

Hoffmann Thomas J TJ Choquet Hélène H Yin Jie J Banda Yambazi Y Kvale Mark N MN Glymour Maria M Schaefer Catherine C Risch Neil N Jorgenson Eric E

Genetics 20180814 2

Body mass index (BMI), a proxy measure for obesity, is determined by both environmental (including ethnicity, age, and sex) and genetic factors, with > 400 BMI-associated loci identified to date. However, the impact, interplay, and underlying biological mechanisms among BMI, environment, genetics, and ancestry are not completely understood. To further examine these relationships, we utilized 427,509 calendar year-averaged BMI measurements from 100,418 adults from the single large multiethnic Gen ...[more]

PMID: 30108127

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Project description:Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ?ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings ?across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women's Health Initiative (WHI).We identified a genome-wide significant association in MESA Hispanics-rs12253976 in KLF6 (beta?=?5.792 kg/m(2) per-allele, 95 % confidence interval (CI): 3.885, 7.698; p?=?3.43?×?10(-9))-and suggestive SNPs with p?<?5?×?10(-6) in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta?=?-1.111 kg/m(2), 95 % CI: -1.578, -0.645; p?=?3.33?×?10(-6)) and WHI Hispanics (beta?=?-0.304 kg/m(2), 95 % CI: -0.613, 0.006; p?=?0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10(-3)) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta?=?1.104 kg/m(2), 95 % CI: 0.643, 1.564; p?=?2.85?×?10(-6)) and WHI African Americans (beta?=?0.219 kg/m(2), 95 % CI: -0.021, 0.460; p?=?0.074).Two BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.

Project description:ImportancePeople with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown.ObjectiveTo assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them.Design, setting, and participantsUsing a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018.Main outcomes and measuresThe primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways.ResultsGenome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways.Conclusions and relevanceIn this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

Project description:ImportanceThe incidence of ischemic stroke among young adults is rising and is potentially due to an increase in stroke risk factors occurring at younger ages, such as obesity.ObjectivesTo investigate whether childhood body mass index (BMI) and change in BMI are associated with adult ischemic stroke and to assess whether the associations are age dependent or influenced by birth weight.Design, setting, and participantsThis investigation was a population-based cohort study of schoolchildren born from 1930 to 1987, with follow-up through national health registers from 1977 to 2012 in Denmark. Participants were 307?677 individuals (8899 ischemic stroke cases) with measured weight and height at ages 7 to 13 years. The dates of the analysis were September 1, 2015, to May 27, 2016.Main outcomes and measuresChildhood BMI, change in BMI, and birth weight. Ischemic stroke events were divided into early (?55 years) or late (>55 years) age at diagnosis.ResultsThe study cohort comprised 307?677 participants (approximately 49% female and 51% male). During the study period, 3529 women and 5370 men experienced an ischemic stroke. At all ages from 7 to 13 years, an above-average BMI z score was positively associated with early ischemic stroke. At age 13 years, a BMI z score of 1 was associated with hazard ratios (HRs) of 1.26 (95% CI, 1.11-1.43) in women and 1.21 (95% CI, 1.10-1.33) in men. No significant associations were found for below-average BMI z scores. Among children with above-average BMI z scores at age 7 years, a score increase of 0.5 from ages 7 to 13 years was positively associated with early ischemic stroke in women (HR, 1.10; 95% CI, 1.01-1.20) and in men (HR, 1.08; 95% CI, 1.00-1.16). Similarly, among children with below-average BMI z scores at age 7 years, a score increase of 0.5 from ages 7 to 13 years was positively associated with early ischemic stroke in women (HR, 1.14; 95% CI, 1.06-1.23) and in men (HR, 1.10; 95% CI, 1.04-1.18). Adjusting for birth weight minimally affected the associations.Conclusions and relevanceIndependent of birth weight, above-average childhood BMI and increases in BMI during childhood are positively associated with early adult ischemic stroke. To avoid the occurrence of early ischemic stroke associated with childhood overweight and obesity, these results suggest that all children should be helped to attain and maintain healthy weights.

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A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci.

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A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci.

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